Hydrophenanthrene carboxylic acids and derivatives thereof and process of making same



Patented Jan. 10, 1950 HYDROPHENANTH ENE; {Minion-v1.16 ACIDS AND, DERIVATIVES THEREOF AND PROCESS OF MAKING Karl Miescher, Iti ehen, and fieorg iinnerlfiasel, Switzerland, assignors to Ciba' Pharmaceutical Products, Inc., Summit, N. J. 7

No Drawing. Application July 23, 1948, Serial No.

40,434. In Switzerland August 27,1947

This invention relates to new hydrophenanthrene 2-carboxyl=ic acids and derivatives thereof such as esters, nitrils andacid amides and their manufacture and more particularly those having the following ring skeleton I in which ring A is aromatic and rings B- and G contains at most one additional double bond, position '7 is unsubstituted, and positions 1' and 2 are either unsubstituted or substituted by a hydrocarbon radical. Octahydrophenanthrene- 2.-c arb oxylic acids and derivatives are illustrative of'the new com-abuses;

y the expression hydrocarbon radical? in positions 1 and 2 is meant an alkyl radical such as methyl, ethyl, or propyl, an alkenyl radical such as alkyl, alkinyl radical such as ethinyl, or an aralkyl radical such as benzyl.

Such hydrophenanthrene-2-carboxylic acids and derivatives thereoi are made by removing the substituent in the 7-i-position from a hydrophenanthrene-2-carboxylic acid, of which the ring A is aromatic and the ring structure contains at most one further double bond, and Which contains in the 7-position a substituent capable of being eliminated and in the 1- and 2-positions hydrogen or hydrocarbon radicals, y v

'T'he s'ubstituent in position 'I which is capable of being. removed m be for example a hydroxyl are hydrox'yl' the hydrogen of which has been Claims. (01. 260 515) 2 ease the starting material as an ad'ditiofial double; bend,,eseecia11y is the 11, 12 panties,

this top can be saturated during the reduct on The el mination r sm aimed gr up is, acq iplished, for eiranip'le by diazdmzanen and heating while halogen atoms are removed by reduction.

from substituted, an amino group or a halogen atom.

The removal of free hydroizyl groupsorsubstitut'ed hydroxyl groups, for example those ,e'ster'ifie'd with, aliphatic of aromatic acids such as acetic, propionic or ben'zoic acids, orthose' or calcium-hydroxides, under more or less ele-' vated hydrogen pressure and teniper'ature'. Iii

'Fiirthrmore the hydrophenanthreiie-2-oarboiylic acids and their derivatives are obtained l-keto hydrophenanthrene-2-carbo5lic acids and their derivativesin which ring A is aromatic, the 7 position is occupied by hydrogen and the 2-position is occupied by a hydrogen or a hydrocarbon radical and whose ring system contains at most; one additional double bond by removingthe keto group and if desired hydrogenating the ethylene double bond;

The removal of the keto group is accomplished for example by ;means of nascent hydrogen formed electrolytically; or bybiochemical methods or catalytically activated hydrogen or through-reaction with an; organo-metallic com- .pourid Aafoigano-metallic;compounds, organo magnesium halides allsyl or alkinyl alkali metal ,compoundsgandthelike are employed. In; the reactionorgano-m'et all-ic compounds a hydrocarbon radical, for example an. alkyl radical such as methyl, ethyl or propyl or an alkenyl radical such as allyl, an alk-i-nyl radical; such as ethi-nyl or an aralkyl radical such as benayl is introduced into the 1-position withtheformation of a'tertiary carbinol. From the resulting tertiary carbinql the newlyjormedjertiary hydroxyl: group is then removed, after first, if necessary reducing multiple bonds in the side chain.

Av further modification of theprocess is carried out by cyclizinga 1 (3' :4-dihydi-onaphthyl-- 1') -butane which contains a free or functionally converted carboxyl group as well as a hydrogen of hydrocarbon radical in the 3-position, a hydrcxyl or keto group as well'as a hydrogen and/or hydrocarbon radical in the i -position and a hydrogen in the 6-po sition of the naphthyl radical, and if necessary hydrogena-ti'ng the compoundsthus obtained.

The butane side chain of the above mentioned startingmaterial contains inthe 3-position in "is hydrogenated.

radical for example an alkyl radical, such as methyl, ethyl or propyl, an alkenyl radical such as alkyl or an aralkyl radical such as benzyl. If

. the side chain contains a hydroxyl' in the 4-posifuric, phosphoric or hydrofluoric acids or mixtures thereof, or also chlorides of phosphorus such as phosphorus oxychloride or oxide of phosphorus such as phosphorus pentoxide, alone or in'pres-' ence of suitable solvents such as acetic acid, ether, or benzene. U I I In a further process for obtaining the desired hydrophenanthrene-Z-carboxylic acids and their derivatives, 3:4 dihydro 1 ethenyl or 3:4 dihydro-l-ethinyl naphthaIene, which have a hydrogen in the 6-position are reacted with azfi-unsaturated monocarboxylic acids or their derivatives and'if the products thus obtained have two; double bonds in rings B and C, atleast one 'As' a ,c-unsaturated monocarboxylic acids? one may use for example acrylic, methacrylimcrotonic, isocrotonic, angelic, tiglic, az'y-dimethylcrotonic, c-methyl p-vinyl acrylic, propiolic and '[i-ethylpropiolic acids derivatives such as the nitril, acid amide and ester.

'Ihe diene synthesismay be carried out in the absence or presence of solvents, such as benzene, toluene, xylene, acetic, propionic or butyric acid .at'morelor less elevated temperature and if desired in the presence of inert gases such as nitro gen. v I f :Finally, the products areobtained also'when 3:4 dihydro 1 ethenyl naphthalene which has a hydrogen in the fi-position is reacted with propiolic acid or its derivatives and, 'if thefpj'rod- Band C, hydrogenating at least one.

u'cts obtained contain twodoublebonds in rings 7 f The procedures employed'in carryingout'this "diene synthesis with ,propiolic acid or its derivatives' are analogous to thosealready described.

Functionally converted carboxyl groups in compounds obtained according to the processes described are converted to free carboxylgroup with hydrolytic agents;

Acids obtained according to the process may be es'terified for example either directly with dia'zomethane or diazoethane or indirectly through the acid halides or salts, or converted to tion. In the examples the same relation exists between parts by weight and parts by volume as exists between grams and cubic centimeters; tem-'- peratures are given in degrees centig'rade.

Example 1 Racemic l ethyl 2 methyl 1:2:3:4:9:10: 11:12 octahydrophenanthrene 2 carboxylic acid:

0.77 part by weight of racemic 'Lmethoxy-lethyl 2 methyl 1:2:314z9z10: hexahydro phenanthrene-Z-carboxylic acid of melting point l68 -170 C. is dissolved in 100 parts by volume of a 0.35% aqueous solution of caustic soda and heated to 80 C. for '4 hours in an autoclave under a pressure of 10 atmospheres of hydrogen in the presence of 2 parts by weight of nickel catalyst. When cool, the contents of the autoclave are extracted with ether, and the alkaline solution is acidified, the acid precipitating in the'for'mof an oil. This 'oil is-then taken up-in ether, and the ether evaporated after. the washing and drying operations. After recrystallization from methanol the race'mic l*-'Tethyl 2 methyl 1:2:3:4:9:10: 11:12 octahydrophenanthrene r 2 carboxylic acid is obtained which melts at 176-178 C.

When there are used as starting materials '7- alkoxy- 1 :2 3 :4 9: 10-hexahydrophenanthrene-2- carboxylic acids which only in the 1- or Z-pcsition contain a hydrocarbon radical, such as an alkyl group, the product is a corresponding :9: 10:11:12-octahydrophenanthrene 2 carboxylic acid with a hydrocarbon radical'in the 1- or 2- f 11: 12 octahydrophenanthrene 2 carboxylic 0.4"part' by weight of methyl'ether 10f; the natural (-l-l'doisynolic acid 7-methoxye ethyl-Z-methyl 1 :2 :3 :4 :19 10 :11 i 12 octahydro phenanthrene-2-carboxylic acid] from estrone is dissolved in 100 parts by volume of dilute caustic soda solution and hydrogenated at 80 C. under 15 atmospheres of hydrogen pressure after the addition of 2 parts by weight of a nickel catalyst. After the completion ofthe hydrogena-f tion, thealkaline solution is extracted with ether and then acidified with dilute hydrochloric acid, the hydrogenation'product separating in the form of'a'n oil. Through the recrystallization of the latter from methanoljthe dextro-rotary 1- ethy1 21-methyl- 1": 2 3 :4 9: 10: 1 12 octahydro'phem anthrene-2-carboxylic acid'is obtainedfwhich melts 217145- 14? C'. and has the specific rotation [e] '=+97 (in alcoholl."

5v I, Erample Racemic 1:2-dimethyl-1: 2 -hexahydrophe nanthrene-Z-carboxylic acid:

-o0on To a Grignard solutionprepared from 1 part by weight of magnesium in 80 parts by volume of ether and '10 parts by volume of methyliodide there are added in a single addition 8' parts by weight of l-oxo-2 methyl l 2:3 :4: 9 IO-hexahydr'ophenanthrene-2-carboxylic acid methyl ester. The reaction mass isthen heated and, when it has cooled down,-decomposed with ice-cold ammonium chloride solution. The reaction product is taken up in a large quantity of ether, washed with dilute hydrochloric acid and water, and the ethereal solution is evaporated. From the residue there is obtained 1-oxy+ :2-dimethyl- 2: 3 :4 9 10 hexahydrophenanthrene-2-carboxylic acid methyl ester and l-methylene-2-methyl -z 2:3:4z9z10-hexahydrophenanthrene 2 carboxylic acid methyl ester. The latter compound is catalytically hydrogenated, the hydrogenation practically coming to a standstill when the double bond of the methylene group is saturated. 1 part by weight of the thus obtained 1: -dimethyl- 1:2:3:4:9:10-hexahydrophenanthrene. 2 carboxylic acid methyl ester is thenheated in an open vessel to 170-180"v C, together with a mixture of 3 parts by Weight of potassimum hydroxide and 10 parts by volume of alcohol in order to hydrolyze the carbomethoxy group. The free :2-d'm1ethy1-1 :2: 3:4: 9 lO-hexahydrophenanthrene2 carboxylic acid is thus obtained.

By reducing the double bond in the 1 2-position of the l:2-dimethyl'-1:2:3: -hexahydrophenanthrene-Z-carboxylic acid methyl ester, for example by means of metallic sodium and alcohol in liquid ammonia and subsequent hydrolysis of the carbomethoxy group the corresponding 1:2-dimethyl- :3: :9: 0: -octahydrophenanthrene-2-carboxylic acid is obtained. The same end product can be made by using, in lieu of the starting material used in this example, l-oxo 2 methy1-1:2:3:4:9:10:11:12- octahydrophenanthrene-2-carboxylic acid methyl ester.

Example 4 Racemic 1-ethyl-2-methyl-1 :2 :3 :4.9:10-hexahydrophenanthrene-2-carboxylic acid:

COOH

CaHa

w parts by weight of 6-(3' :4'-dihydronaphthyl- 1) -4methyl-4-carbomethoxy-hexane-3-one are mixed at 0 C. with 150 parts by volume of icecold concentrated sulfuric acid and stirred at this temperature until dissolution is complete. When the cyclization is finished, the reaction mixture is poured onto ice and the precipitated oily product is taken up in ether. The ethereal solution is Washed neutral and dried and then evaporated to obtain the 1-ethyl-idene-2 -methyl-' 1:'2:3:4:9 :10 hexahydrophenanthrene 2 car boxylic acid methyl ester. This compound is converted into the l-ethyl-2-methyl-lz2z3:4:9:10- hexahydrophenanthrene 2 carboxylic acid methyl ester by hydrogenation in the presence of anickel catalyst. In order to hydrolyze the carbomethoxy group 1 part by weight thereof is heated in an open vessel to -180 C. in a mixture of 3 parts by Weight of potassium hydroxide, 0.5 part by weight of water and; 5 parts by volume of alcohol. The reaction mixture is then dissolved in water, and acidified with dilute hydrochloric acid to obtain 1-ethyl-2-methyl- 1:2:3:4:9:10 hexahydrophenanthrene 2 car boxylic acid.

In lieu of performing direct cyclization, one may first reduce the starting material, for example with catalytically activated or nascent hydrogen or with an aluminum alcoholate or aluminum phenolate in the presence of isopropyl alcohol, to obtain'6 (3z4' dihydronaphthyl 1') -4-methyl -4-carbomethoxy-hexane-3-01, and then treat this compound with a cyclicizing agent. The primary conversion-into a carbinol may alternatively be performed by the'reaction with an organo-metal compound, whereby the C=O group in 3-position is converted into the group wherein R stands, for example, for an alkyl, aralkyl' or aryl group.

The starting material can be obtained, for example, as-follows: A mixture of 15 parts by weight of finely pulverized potassium in 500 parts by volume of benzene is mixed with '74 parts by Weight of a-propionyl-propionic acid methyl ester and heated under an atmosphere of nitrogen until a clear solution is obtained. There are then added to the cooled solution 120 parts by weight of l-(fi-bromethyl) -3:4-dihydronaphthalene whereupon it is refluxed for several hours.

When it has cooled off, it is acidified with glacial acetic acid, extracted with ether, washed neutral, dried and evaporated. The resultant 6-(3:4'- dihydronaphthyl 1') 4 methyl 4 carbo methoxy-hexane-S-one can be distilled in a high vacuum without being decomposed.

Example 5 1:2 3 24:9 10 z 11 :12 octahydrophenanthrene Z-carboxylic acid:

COOH

10 parts by weight of 1-etheny1-3:4-dihydr0 naphthalene are boiled overnight in a, Claisen flask with 10 parts by weight of propiolic acid methyl ester in an atmosphere of nitrogen. From the reaction mixture, the unchanged starting materials and then also the newly formed tetrahydrophenanthrene 2 carboxylic acid methyl ester are distilled off. In order to saturate the two newly formed double bonds in ring 0 of the latter compound with hydrogen, 2 parts by weight thereof are hydrogenated in the presence of 1 part by weight of a palladium catalyst and 50 parts by volume of glacial acetic acid.

Earample 6 3 9: 10: 11: 12 e octahydrophenanthrene i: 2-carboxylic acid:

1 29' parts by weight of I-ethenyI-SA-dihydm naphthalene areadded at C. to 100 partsby volume of hydrogen bromide in ether, 40 parts by 7 weight of acrylic acid are carefully added and the mixture is allowed to stand at room'temperature for some time, while the newly formed hexahydrophenanthrene-Z-carboxylic acid precipitates; 1 part by weight thereof .is dissolved in' parts by volume of glacial acetic acid and,

agitated in the presence of 1 part by weight of a palladium catalyst under hydrogen. The hydrogenation ceases when the quantity of hydrogen calculated for 1 molecular equivalent is absorb'ed. .1:'2:3:4:9:10:1l:12 octahydrophenan threne-Z-carboxylic acid is obtained when the catalyst is removed by filtration andthe solvent evaporated. I

What we claim is: 1. A hydrophenanthrene-2-carboxylic acid in which ring A is aromatic, and positions 1 and 2 are occupied by a member. of the group consist ing of hydrogen and lower alkyl and in which the ring skeleton contains at most one additional double bond andno further substituents.

2. A 1:2:3:4:9:10:l1:12 octahydrophenanthrene-2-carboxylic acid in which positions 1 and 2am occupied by a member of the group consisting of hydrogen and lower alkyl and in which the ring skeleton contains no further substituents.

3. A 1-ethyl-2-methyl-1:2:3:4:9:10:11:12-0ctahydrophenanthrene -2-carboxylic acid.

4. The process of preparing hydrophenanthrene-Z-carboxylic acids in which ring A is aromatic, and positions 1 and 2 are occupied by a member of the group consisting of hydrogen and lower alkyl and in which the ringskeleton contains at most one additional double bond and no further substituent, which comprises reacting hydrophenanthrene-2-carboxylic acids and their derivatives in which ring A is aromatic, position 7 is occupied by an etherified hydroxyl and positions 1 and 2 are occupied by a member of the group consisting of hydrogen and lower alkyl with hydrogen over a hydrogenation catalyst at a temperatureof about C. and a pressure of about 15 atmospheres. 7 1 5,;The process of preparing.1-ethyl-2-methyl l:2:3:4:9:10:1 1 :12 octahydrophenanthrene- 2- carboxylic acid which comprises reacting- '7- methoxy- 1 -ethyl-2-methyl- 1 :2 :314 :9 IO-hexahydrophenanthrene-2-carboxylic acid with hydrogen and a hydrogenation catalyst at a temperature of about 80 C. and a pressure of about 15 atmospheres.

' I KARL MIESCHER.

GEORG ANNER.

' REFERENCES CITED The following references are of record in the file'of this patentz J. Chem. soe, vol. 1946, pp. 

1. A HYDROPHENANTHRENE-2-CARBOXYLIC ACID IN WHICH RING A IS AROMATIC, AND POSITIONS 1 AND 2 ARE OCCUPIED BY A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL AND IN WHICH THE RING SKELETON CONTAINS AT MOST ONE ADDITIONAL DOUBLE BOND AND NO FURTHER SUBSTITUENTS. 